The present application relates to a process for producing prostacyclin derivatives and novel intermediate compounds useful in the process.
Prostacyclin derivatives are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, and bronchodilation.
For convenience, the novel prostacyclin derivatives will be referred to by the trivial, art-recognized system of nomenclature described by N. A. Nelson, J. Med. Chem. 17:911 (1974) for prostaglandins. Accordingly, all of the novel prostacyclin derivatives herein will be named as 9-deoxy-PGF1-type compounds.
The prostacyclin derivatives prepared by the method disclosed in the ""075 patent are as follows: 
wherein L1 is xcex1-R3:xcex2-R4, xcex1-R4: xcex2-R3, or a mixture of xcex1-R3:xcex2-R4 and xcex1-R4: xcex2-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen or fluoro;
wherein M1 is xcex1-OH: xcex2-R5 or xcex1-R5: xcex2-OH, wherein R5 is hydrogen or methyl;
wherein R7 is
(1) -CmH2m-CH3, wherein m is an integer from one to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 are hydrogen or methyl, being the same or different,
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl,
(4) cisxe2x80x94CH=CH-CH2-CH3,
(5) (CH2)2-CH(OH)-CH3, or
(6) -(CH2)3xe2x80x94CH=C(CH3)2;
wherein -C(L2)-R7 taken together is
(1) (C4-C7)cycloalkyl optionally substituted by one to 3 (C1-C5) alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
wherein R8 is hydroxy, hydroxymethyl, or hydrogen;
wherein
(1) R20, R21, R22, R23, and R24 are all hydrogen with R22 being either xcex1-hydrogen or xcex2-hydrogen,
(2) R20 is hydrogen, R21 and R22 taken together form a second valence bond between C-9 and C-6a, and R23 taken together form a second valence bond between C-8 and C-9 or are both kydrogen, or
(3) R22, R23, and R24 are all kydrogen, with R22 being either xcex1-hydrogen or xcex2-hydrogen, and
(a) R20 and R21 taken together are oxo, or
(b) R20 is kydrogen and R21 is hydroxy, being xcex1-hydroxy or xcex2-hydroxy;
wherein X1 is
(1) -COOR1, wherein R1 is
(a) hydrogen,
(b) (C1-C12)alkyl,
(c) (C3-C10)cycloalkyl,
(d) (C6-C12)aralkyl,
(e) phenyl, optionally substituted with one, 2 or 3 chloro or (C1-C1)alkyl,
(f) phenyl substituted in the para position by
(i) -NH-CO-R25,
(ii) -CO-R26,
(iii) -O-CO-R54, or
(iv) -CH=N-NH-CO-NH2 wherein R25 is methyl, phenyl, acetamidophenyl, benzamidophenyl, or -NH2: R26 is methyl, phenyl, -NH2, or methoxy; and R54 is phenyl or acetamidophenyl; inclusive, or
(g) a pharmacologically acceptiable cation;
(2) -CH2OH,
(3) -COL4, wherein L4 is
(a) amino of the formula - - NR51R52, wherein R51 and R52 are
(i) hydrogen,
(ii) (C1- C12)alkyl,
(iii) (C3-C10)cycloalkyl,
(iv) (C7- C12)aralkyl,
(v) phenyl, optionally substituted with one, 2 or 3 chloro, (C1-C3)alkyl, hydroxy, carboxy, (C2-C5)alkoxycarbonyl, or nitro,
(vi) (C2-C5)carboxyalkyl,
(vii) (C2-C5)carbamoylalkyl,
(viii) (C2-C5)cyanoalkyl,
(ix) (C3-C6)acetylalkyl,
(x) (C7-C11)benzoalkyl, optionally substituted by oe, 2 or 3 chloro, (C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, carboxy, (C2-C5)alkoxycarbonyl, or nitro,
(xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C1-C3)alkyl, or (C1-C3)alkoxy,
(xii) (C6-C9)pyridylalkyl optionally substituted by one, 2 or 3 chloro, (C1-C3)alkyl, hydroxy, or (C1-C3)alkyl,
(xiii) (C1-C4)kydroxyalkyl,
(xiv) (C1-C4)dihydroxyalkyl,
(xv) (C1-C4)trihydroxyalkyl,
with the further proviso that not more than one of R51 and R52 is other than hydrogen or alkyl,
(b) cycloamino selected from the group consisting of lyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (C1-C12)alkyl of one to 12 carbon atoms, inclusive,
(c) carbonylamino of the formula -NR53COR51, wherein R53 is hydrogen or (C1-C4)alkyl and R51 is other than hydrogen, but otherwise as defined above,
(d) sulfonylamino of the formula -NR53SO2R51, wherein R51 and R53 are as defined in (c),
(4) -CH2NL2L3, wherein L2 and L3 are kydrogen or (C1-C4)alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when X1 is -CH2NL2L3,
wherein Y1 is trans-CH=CH-, cis-CH=CH-, CH2CH2-, or -Cxe2x89xa1C-; and
wherein Z4 is -CH2- or -(CH2)-CF2, wherein ƒ is zero, one, 2 or 3.
When X1 is -COOR1 of the Formulac in the ""075 patent, the novel compounds so described are used for the purposes described and are in free acid form, in ester form, or in pharmacologically acceptable salt form. When the ester form is used, the ester is any of those within the above definition of R1. However, it is preferred that the ester be alkyl of one to 12 carbon atoms, inclusive. Of the alkyl esters, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system; and straight-chain oxtyl, nonyl, decyl, undecyl, and dodecyl are especially preferred for prolonged activity.
Pharmacologically acceptable salts of the novel prostagladin analogs of this invention for the purposes described are those with pharmacologically acceptiable metal cations, ammonia, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are within the scope of this invention.
Pharmacologically acceptable amine cations are those derived from primary, secondary, and tertiary amines. Example of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, xcex1-phenylethylamine, xcex2-phenylethylamine, ethylenediamine, diethylenetriamine, adamantylamine, and the like aliphatic, cycloaliphatic, araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazie, and lower-alkyl derivatives thereto, e.g., 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl,-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxymethyl) aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, galactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrie, procaine, and the like. Further useful amine salts of the basic amino acid salt, e.g., lysie and arginine.
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.
U.S. Pat. No. 4,306,075 discloses methods for making prostacyclin derivatives. However, these and other known processes involve a large number of steps. It is an object of the present invention to provide an improved method of preparing prostacyclin derivatives involving fewer steps.
The present invention relates to a process for preparing 9-deoxy-PGF1-type compounds by a process that is stereoselective and requires fewer steps than the prior art. The invention also relates to novel intermediates prepared during the synthesis of the 9-deoxy-PGF1-type compounds.
In one embodiment, the present invention relates to an improved stereoselective method for making 9-deoxy-PGF1-type compounds comprising converting a compound of the formula: 
into a compound of the following formula: 
wherein Z is O, S, CH2, or NR8 in which R8 is H, alkyl or aryl;
X is H, CN, OR9, or COOR9 in which R9 is alkyl, THP or TBDMS;
wherein n is 0, 1, 2, or 3;
wherein Y1 is trans-CHxe2x95x90CHxe2x80x94, cis-CHxe2x95x90CHxe2x80x94, xe2x80x94CH2(CH2)mxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94; m is 1,2, or 3;
wherein R1 is an alcohol protecting group;
wherein R7 is
(1) xe2x80x94CpH2pxe2x80x94CH3, wherein p is an integer from one to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 are hydrogen or methyl, being the same or different,
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl,
(4) cis-CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH3,
(5) xe2x80x94(CH2)2xe2x80x94CH(OH)xe2x80x94CH3, or
(6) xe2x80x94(CH2)3xe2x80x94CHxe2x95x90C(CH3)2;
wherein xe2x80x94C(L1)xe2x80x94R7 taken together is
(1) (C4-C7)cycloalkyl optionally substituted by one to 3 (C1-C5) alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
wherein M1 is xcex1-OH:xcex2-R5 or xcex1-R5:xcex2-OH, wherein R5 is hydrogen or methyl; and
wherein L1 is xcex1-R3:xcex2-R4, xcex1-R4:xcex2-R3, or a mixture of xcex1-R3:xcex2-R4 and xcex1-R4:xcex2-R3,
wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen or fluoro.
Preferably, the above conversion is carried out through cobalt-mediated cyclization, in which a complex is formed with the alkynyl group of the starting compound, which decomposes upon heating to form a tricyclic structure. More preferably, this cyclization is carried out by reacting Co2(CO)8 with the above compound of the formula: 
using a suitable non-reactive solvent. Preferably, the non-reactive solvent is a chlorinated solvent, a hydrocarbon solvent, or an aromatic solvent. More preferably, the non-reactive solvent is CH2Cl2, toluene, isooctane, and heptane.
In the case of carrying out the cobalt-mediated cyclization with CH2Cl2, after reacting Co2(CO)8 with the above compound of the formula: 
in the presence of CH2Cl2 to form a complex with the alkynyl group, preferably the CH2Cl2 is removed in a subsequent step and replaced with CH3CN followed by heating in an inert gas atmosphere, such as argon, nitrogen, or carbon monoxide, which decomposes the complex to form the above tricyclic compound.
Although Co2(CO)8 contributes a carbonyl during the reaction, it is not necessary to react equal amounts of the starting compound of the above formula and Co2(CO)8. It is also possible to use the Co2(CO)8 in a catalytic way, by introducing a relatively small amount of Co2(CO)8 and also introducing CO into the reaction mixture (e.g., by bubbling CO into the reaction mixture) in the presence of light which catalyzes the transfer of CO through a Co-mediated complex formed with the above compound of the formula: 
In another preferred embodiment, the present invention relates to an improved stereoselective method for making 9-deoxy-PGF1-type compounds comprising the following reaction: 
wherein n is 0, 1, 2, or 3;
wherein Y1 is trans-CHxe2x95x90CHxe2x80x94, cis-CHxe2x95x90CHxe2x80x94, xe2x80x94CH2(CH2)mxe2x80x94, or xe2x80x94Cxe2x95x90Cxe2x80x94; m is 1,2, or 3;
wherein R1 is an alcohol protecting group;
wherein R7 is
(1) xe2x80x94CpH2pxe2x80x94CH3, wherein p is an integer from one to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 are hydrogen or methyl, being the same or different,
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)allyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl,
(4) cis-CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH3,
(5) xe2x80x94(CH2)2xe2x80x94CH(OH)xe2x80x94CH3, or
(6) xe2x80x94(CH2)3xe2x80x94CHxe2x95x90C(CH3)2;
wherein xe2x80x94C(L1)xe2x80x94R7 taken together is
(1) (C4-C7)cycloaklyl optionally substituted by one to 3 (C1-C5) alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
wherein M1 is xcex1-OH:xcex2-R5 or xcex1-R5:xcex2-OH, wherein R5 is hydrogen or methyl;
wherein L1 is xcex1-R3:xcex2-R4, xcex1-R4:xcex2-R3, or a mixture of xcex1-R3:xcex2-R4 and xcex1-R4:xcex2-R3,
wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen or fluoro.
The present invention also relates to a method of making the following compounds utilizing the foregoing reaction: 
wherein R1 is in each case an independently selected alcohol protecting group. Preferred alcohol protecting groups are tertiary butyl dimethyl sily (TBDMS) and tetra hydro pyranyl (THP).
The present invention also relates to the following novel intermediate compounds: 
wherein X, Z, Y1, M1, L1, R1 and R7 are as defined above.
The present invention is further illustrated by, though in no way limited to, the following examples.